Normal function of the immune system requires that B cells develop an appropriate repertoire of receptors that can recognize a diverse array of antigens. Engagement of these B cell antigen receptors (BCR) initiates a program of cellular activation resulting in proliferation and differentiation into plasma cells and memory B cells. B cell activation is initiated and dependent on the Syk protein tyrosine kinase (PTK). Normal B cell function requires the appropriate enzymatic activation of Syk for a variety of biochemical pathways-including increases in free cytoplasmic calcium level, the activation of small G proteins, such as Ras and Rho, and the transcriptional activation of NFkappaB. While the absence of Syk abrogates the ability of B cells to develop, normal enzymatic activation of Syk is also required to coordinate this cascade of signaling events. Aberrant activation, the absence of subsets of signaling pathways, or inappropriate integration of the divergent signaling mechanisms may result in cell death, receptor unresponsiveness (anergy), or uncontrolled cell growth (tumorigenesis). in turn, these cellular and developmental abnormalities may contribute to autoimmune disorders resulting in vasculitis and autoimmune disorders involving the kidney to give rise to glomerulonephritis and/or - the pancreas resulting in diabetes mellitus. While we and others have previously defined mechanisms of Syk activation mediated through tyrosine phosphorylation of the Syk catalytic domain, this grant will investigate a novel regulatory mechanism for controlling Syk activity through its hinge domain. Specifically, we will analyze the function of the Syk hinge domain in inhibiting the basal enzymatic activity of Syk and its function in integrating and coordinating the downstream signaling pathways activated by the BCR. As Syk is also required for efficient phagocytosis in macrophages, killing in natural killer cells, and function of the high affinity IgE receptor in mast cells, these studies will likely provide greater insights into the receptor function expressed on a variety of immune cells.